Whole-genome sequencing holds the key to the success of gene-targeted therapies.

Rare genetic disorders affect as many as 3%-5% of all babies born. Approximately 10,000 such disorders have been identified or hypothesized to exist. Treatment is supportive except in a limited number of instances where specific therapies exist. Development of new therapies has been hampered by at least two major factors: difficulty in diagnosing diseases early enough to enable treatment before irreversible damage occurs, and the high cost of developing new drugs and getting them approved by regulatory agencies. Whole-genome sequencing (WGS) techniques have become exponentially less expensive and more rapid since the beginning of the human genome project, such that return of clinical data can now be achieved in days rather than years and at a cost that is comparable to other less expansive genetic testing. Thus, it is likely that WGS will ultimately become a mainstream, first-tier NBS technique at least for those disorders without appropriate high-throughput functional tests. However, there are likely to be several steps in the evolution to this end. The clinical implications of these advances are profound but highlight the bottlenecks in drug development that still limit transition to treatments. This article summarizes discussions arising from a recent National Institute of Health conference on nucleic acid therapy, with a focus on the impact of WGS in the identification of diagnosis and treatment of rare genetic disorders.

The Progress and Future of US Newborn Screening.

Progress in newborn screening (NBS) has been driven for 60 years by developments in science and technology, growing consumer advocacy, the actions of providers involved in the care of rare disease patients, and by federal and State government funding and policies. With the current explosion of clinical trials of treatments for rare diseases, the pressure for expansion has grown, and concerns about the capacity for improvement and growth are being expressed. Genome and exome sequencing (GS/ES) have now opened more opportunities for early identification and disease prevention at all points in the lifespan. The greatest challenge facing NBS stems from the conditions most amenable to screening, and new treatment development is that we are screening for rare genetic diseases. In addition, understanding the spectrum of severity requires vast amounts of population and genomic data. We propose recommendations on improving the NBS system and addressing specific demands to grow its capacity by: better defining the criteria by which screening targets are established; financing the NBS system's responsiveness to opportunities for expansion, including engagement and funding from stakeholders; creating a national quality assurance, data, IT, and communications infrastructure; and improving intra-governmental communications. While our recommendations may be specific to the United States, the underlying issues should be considered when working to improve NBS programs globally.

Ethical Issues Surrounding Newborn Screening.

It would be difficult to overestimate the importance of persistent, thoughtful parents and their importance in the development of treatments for their children's rare disorders. Almost a century ago in Norway, observant parents led a brilliant young physician-scientist to his discovery of the underlying cause of their children's profound developmental delay-i.e., phenylketonuria, or PKU. Decades later, in a recovering war-ravaged Britain, an equally persistent mother pressed the scientists at Birmingham Children's Hospital to find a way to treat her seriously damaged daughter, Sheila, who suffered from PKU. Living on the financial edge, this mother insisted that Bickel and colleagues develop such a diet, and she volunteered Sheila to be the patient in the trial. The scientists concluded that the low phenylalanine diet helped but needed to be started very early-so, newborn screening was born to permit the implementation of this. Many steps brought us to where we are today, but these courageous parents made it all begin.

Maximizing the Benefit of Life-Saving Treatments for Pompe Disease, Spinal Muscular Atrophy, and Duchenne Muscular Dystrophy Through Newborn Screening: Essential Steps.

IMPORTANCE: Newborn screening (NBS) identifies infants with specific congenital disorders for which earlier intervention cannot only prevent a lifetime of chronic disability but also, most importantly, save lives. In this article, we discuss complexities associated with NBS processes in the United States, with a focus on challenges in neuromuscular disorders. OBSERVATIONS: As new interventions for neuromuscular disorders become available, the clinical community must prepare to overcome the challenges of adding new diseases to screening panels and understand the rigorous evidence review at the federal level and the complex process of state-level implementation. In this regard, NBS programs for Pompe disease and spinal muscular atrophy can guide the path of Duchenne muscular dystrophy and other neuromuscular disorders as future candidates for NBS. CONCLUSIONS AND RELEVANCE: The availability of advanced screening methods, the emergence of effective treatment, and the support of professional organizations may facilitate the expansion of NBS, such that an increasing number of infants can be identified in the newborn period who will benefit from life-saving interventions.

Dysphagia in Parkinson's Disease Improves with Vocal Augmentation.

While voice-related disorders in Parkinson's disease (PD) are commonly discussed in the literature, dysphagia in PD is less widely published. Vocal fold augmentation, including injection laryngoplasty (IL), is a well-established treatment for glottal insufficiency (Cates et al. in Otolaryngol Head Neck Surg 155(3):454-457, 2016). This study aimed to observe the effects of IL in PD patients with vocal bowing, with or without therapy, on glottic closure and patient-reported dysphagia outcomes. The study design was based on retrospectively collected database and cohort-case series. PD patients selected for retrospective review over a 2-year period were referred and evaluated in the Voice, Swallowing, and Airway multidisciplinary clinic by speech language pathologist and laryngologist, and were undergoing IL. Charts were reviewed for age, gender, Body Mass Index (BMI), onset of PD, and Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part 3 (MDS-UPDRS) scoring. We compared pre/postoperatively (> 1 < 3 months) using validated patient-reported outcome tools: Reflux Symptom Index (RSI), Glottal Function Index (GFI), Eating Assessment Tool-10 (EAT), and stroboscopic examinations. The study included 14 patients undergoing 22 IL or 1.6 IL/patient: mean age 70 years (63-80), 100% male, and BMI 25.9 ± 4.3 (mean ± SD). MDS-UPDRS scoring 33 ± 20 (moderate severity), with time between PD diagnosis and IL 8 ± 10 years. All patients had pre- and post-stroboscopic examinations; however, only 4:14 underwent formal swallowing evaluation. Overall, 14 IL patients improved on patient-reported measures (ΔRSI = 4; ΔGFI = 3; ΔEAT = 4). Based on the findings of the study, we conclude that PD is a progressive neurodegenerative condition with dysphagia. The presented pilot data suggest that IL may be considered as a beneficial adjunct for PD patients with glottal insufficiency. LEVEL OF EVIDENCE: 4.

Including ELSI research questions in newborn screening pilot studies.

BACKGROUND: The evidence review processes for adding new conditions to state newborn screening (NBS) panels rely on data from pilot studies aimed at assessing the potential benefits and harms of screening. However, the consideration of ethical, legal, and social implications (ELSI) of screening within this research has been limited. This paper outlines important ELSI issues related to newborn screening policy and practices as a resource to help researchers integrate ELSI into NBS pilot studies. APPROACH: Members of the Bioethics and Legal Workgroup for the Newborn Screening Translational Research Network facilitated a series of professional and public discussions aimed at engaging NBS stakeholders to identify important existing and emerging ELSI challenges accompanying NBS. RESULTS: Through these engagement activities, we identified a set of key ELSI questions related to (1) the types of results parents may receive through newborn screening and (2) the initiation and implementation of NBS for a condition within the NBS system. CONCLUSION: Integrating ELSI questions into pilot studies will help NBS programs to better understand the potential impact of screening for a new condition on newborns and families, and make crucial policy decisions aimed at maximized benefits and mitigating the potential negative medical or social implications of screening.

A recent history of opioid use in the US: Three decades of change.

BACKGROUND: The opioid epidemic in the United States is a problem that has developed over decades. While clinical, regulatory, and legislative changes have been implemented to combat this issue, changes will not be immediate. Moreover, the changes that have been carried out may have unintended negative consequences such as increased use of illicit opioids (e.g., heroin and synthetics) and challenges in effective and appropriate pain management. OBJECTIVES: This review focuses on the last three decades and presents key changes the United States has seen in the use of opioids. Conclusions/Importance: There have been numerous policy changes and programs aimed at decreasing opioid use and abuse in the United States; however, it will take a major shift in the mindset of clinicians, the general public, and policy makers to alleviate this epidemic.

Using advanced wound care and hyperbaric oxygen to manage wound complications following treatment of vulvovaginal carcinoma.

Postoperative management of patients with vulvar cancer is associated with a high incidence of poor wound healing and radiation -induced late tissue necrosis. This case series demonstrates the impact on wound healing with the use of hyperbaric oxygen therapy and advanced wound care following radical vulvectomy and/or radiation therapy. A retrospective case series was performed of all patients from 2016 to 2017 with lower genital cancer who underwent radical surgery with or without chemoradiation treatment, experienced wound dehiscence or late tissue radionecrosis, and were treated with advanced wound care, including hyperbaric oxygen therapy (HBO). Five patients were included with a mean age of 63; four had squamous cell carcinoma and one patient had vaginal adenocarcinoma secondary to prior diethylstilbestrol exposure. Three patients underwent radical vulvectomy. All received pelvic radiation therapy, subsequently experienced wound complications, and were managed with advanced wound care and HBO. The mean reduction in wound area at the final wound follow up visit after completion of HBO therapy was found to be 76%, ranging 42-95%, with an average follow up of five months. The mean number of HBO sessions per patient was 58. Complete tissue granulation or significant improvement in tissue radionecrosis was present in all patients. Advanced wound care and hyperbaric oxygen therapy are beneficial in the management of postoperative wound complications. Prospective studies are needed to identify the optimal use of perioperative hyperbaric oxygen and appropriate wound care for patients with gynecologic malignancies.

Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of alpha motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron 1 gene (SMN1). In humans, a nearly identical copy gene, SMN2, is present. Because SMN2 has been shown to decrease disease severity in a dose-dependent manner, SMN2 copy number is predictive of disease severity. OBJECTIVE: To develop a treatment algorithm for SMA-positive infants identified through newborn screening based upon SMN2 copy number. METHODS: A working group comprised of 15 SMA experts participated in a modified Delphi process, moderated by a neutral third-party expert, to develop treatment guidelines. RESULTS: The overarching recommendation is that all infants with two or three copies of SMN2 should receive immediate treatment (n = 13). For those infants in which immediate treatment is not recommended, guidelines were developed that outline the timing and appropriate screens and tests to be used to determine the timing of treatment initiation. CONCLUSIONS: The identification SMA affected infants via newborn screening presents an unprecedented opportunity for achievement of maximal therapeutic benefit through the administration of treatment pre-symptomatically. The recommendations provided here are intended to help formulate treatment guidelines for infants who test positive during the newborn screening process.

From a Single Child to Uniform Newborn Screening: My Lucky Life in Pediatric Medical Genetics.

Mike, a memorable young patient with untreated phenylketonuria, as well as others affected by genetic disorders that could be treated if diagnosed in infancy, launched my six-decade career. This autobiographical article reflects on my childhood, early research, and professional experiences in pediatric genetics. My laboratory research focused on inborn errors of metabolism, including the glycogen storage diseases. My effort to organize newborn screening through the recommended uniform screening panel shaped and standardized newborn screening nationwide. Looking ahead, the expansion of whole-genome and whole-exome sequencing into newborn screening raises ethical and policy issues regarding informed consent procedures and the storage and use of residual blood spots.

Duchenne Muscular Dystrophy Newborn Screening, a Case Study for Examining Ethical and Legal Issues for Pilots for Emerging Disorders: Considerations and Recommendations.

Duchenne muscular dystrophy (DMD/Duchenne) is one of the ten most severe and common pediatric genetic diseases and affects an estimated 1 in every 5000 male births. While Duchenne is a 100% fatal disease, the clinical community has demonstrated that immediate identification and early clinical interventions can add years, even decades to an individual's life span. In anticipation of the changing therapeutic landscape for the Duchenne community, Parent Project Muscular Dystrophy established a newborn screening (NBS) initiative. This initiative included a Bioethics and Legal Issues Workgroup to consider the bioethics and legal issues of NBS for Duchenne. The workgroup's discussion focused only on Duchenne NBS and met through conference calls over a one-year period of time seeking consensus on various identified issues. This article reports on the findings and recommendations from that workgroup.

Newborn screening for Duchenne muscular dystrophy in China: follow-up diagnosis and subsequent treatment.

BACKGROUND: Newborn screening for Duchenne muscular dystrophy (DMD) is currently being initiated in Zhejiang Province, China and is under consideration in other countries, including the United States. As China begins to implement DMD newborn screening (DMD-NBS), there is ongoing discussion regarding the steps forward for follow up care of positively identified patients as well as false positive and false negative results. DATA SOURCES: Relevant papers related to DMD-NBS, and NBS in China were reviewed in PubMed. RESULTS: The current state of DMD-NBS is discussed, along with the steps needed to effectively screen infants for this disease in China, recommendations for establishment of follow up care in patients with positive and negative screens, and measurement of patient outcomes. CONCLUSIONS: Zhejiang Province, China is ready to implement DMD-NBS. Future challenges that exist for this program, and other countries, include the ability to track patients, assist with access to care, and ensure adequate follow-up care according to evidence-based guidelines. In addition, China's large rural population, lack of specialty providers, and difficulty in educating patients regarding the benefits of treatment create challenges that will need to be addressed.

The Management of Domestic Animal Bites to the Hand.

Hand bites from domestic animals are extremely common. Though many may initially appear benign, it is important for treating physicians to be aware of the factors that place patients sustaining animal bites at additional risk for infection. As clinicians, we must be able to efficiently diagnose and treat these patients properly to avoid the morbidity that animal bites can provoke. The current paper reviews the evaluation and management of domestic animal bites to the hand.

Efficacy of intravenous administration of combined acid suppressants in healthy dogs.

BACKGROUND: Short-term intravenous co-administration of famotidine and pantoprazole is used by some veterinarians to treat gastrointestinal bleeding in critically ill dogs. However, clinical studies have not evaluated the efficacy of combination acid suppressant treatment in dogs. HYPOTHESIS/OBJECTIVES: To compare the effect of intravenous co-administration of famotidine and pantoprazole to monotherapy with pantoprazole on intragastric pH in dogs. We hypothesized that single agent pantoprazole would be more effective than combination with famotidine. ANIMALS: Twelve healthy adult colony dogs. METHODS: Randomized, 2-way crossover design. All dogs received placebo (0.9% saline) for 24 hours followed by 1.0 mg/kg i.v. q12h pantoprazole or combination treatment with famotidine and pantoprazole for 3 consecutive days. Intragastric pH monitoring was used to continuously record intragastric pH for 96 hours beginning on day 0 of treatment. Mean percentage time (MPT) that intragastric pH was ≥3 and ≥4 were compared between groups using ANOVA with a posthoc Tukey-Kramer test (α = 0.017). RESULTS: The MPT ± standard deviation intragastric pH was greater than ≥3 and 4 were 79 ± 17% and 68 ± 17% for pantoprazole and 74 ± 19% and 64 ± 23% for combination treatment, respectively. There were no significant differences in MPT intragastric pH was ≥3 and 4 between groups. Pantoprazole administered alone achieved pH goals established for humans with acid-related disorders. CONCLUSIONS AND CLINICAL IMPORTANCE: These results suggest that short-term combination treatment with famotidine and pantoprazole is not superior to pantoprazole alone for increasing intragastric pH in dogs.

Genetics of epilepsy: The testimony of twins in the molecular era.

OBJECTIVE: Analysis of twins with epilepsy to explore the genetic architecture of specific epilepsies, to evaluate the applicability of the 2010 International League Against Epilepsy (ILAE) organization of epilepsy syndromes, and to integrate molecular genetics with phenotypic analyses. METHODS: A total of 558 twin pairs suspected to have epilepsy were ascertained from twin registries (69%) or referral (31%). Casewise concordance estimates were calculated for epilepsy syndromes. Epilepsies were then grouped according to the 2010 ILAE organizational scheme. Molecular genetic information was utilized where applicable. RESULTS: Of 558 twin pairs, 418 had confirmed seizures. A total of 534 twin individuals were affected. There were higher twin concordance estimates for monozygotic (MZ) than for dizygotic (DZ) twins for idiopathic generalized epilepsies (MZ = 0.77; DZ = 0.35), genetic epilepsy with febrile seizures plus (MZ = 0.85; DZ = 0.25), and focal epilepsies (MZ = 0.40; DZ = 0.03). Utilizing the 2010 ILAE scheme, the twin data clearly demonstrated genetic influences in the syndromes designated as genetic. Of the 384 tested twin individuals, 10.9% had mutations of large effect in known epilepsy genes or carried validated susceptibility alleles. CONCLUSIONS: Twin studies confirm clear genetic influences for specific epilepsies. Analysis of the twin sample using the 2010 ILAE scheme strongly supported the validity of grouping the "genetic" syndromes together and shows this organizational scheme to be a more flexible and biologically meaningful system than previous classifications. Successful selected molecular testing applied to this cohort is the prelude to future large-scale next-generation sequencing of epilepsy research cohorts. Insights into genetic architecture provided by twin studies provide essential data for optimizing such approaches.